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The Albumin in Subarachnoid Hemorrhage (ALISAH) multicenter pilot clinical trial: safety and neurologic outcomes.

ABSTRACT: Human albumin has been shown to exert neuroprotective effects in animal models of cerebral ischemia and humans with various intracranial pathologies. We investigated the safety and tolerability of 25% human albumin in patients with subarachnoid hemorrhage.The Albumin in Subarachnoid Hemorrhage (ALISAH) Pilot Clinical Trial was an open-label, dose-escalation study. We intended to study 4 different dosages of albumin of increasing magnitude (0.625 g/kg: Tier 1; 1.25 g/kg: Tier 2; 1.875 g/kg: Tier 3; and 2.5 g/kg: Tier 4). Each dosage was to be given to 20 adult patients. Treatment was administered daily for 7 days. We investigated the maximum tolerated dose of albumin based on the rate of severe-to-life-threatening heart failure and anaphylactic reaction and functional outcome at 3 months.We treated 47 adult subjects: 20 in Tier 1; 20 in Tier 2; and 7 in Tier 3. We found that doses ranging up to 1.25 g/kg/day×7 days were tolerated by patients without major dose-limiting complications. We also found that outcomes trended toward better responses in those subjects enrolled in Tier 2 compared with Tier 1 (OR, 3.0513; CI, 0.6586-14.1367) and with the International Intraoperative Hypothermia for Aneurysm Surgery Trial cohort (OR, 3.1462; CI, 0.9158-10.8089).Albumin in doses ranging up to 1.25 g/kg/day×7 days was tolerated by patients with subarachnoid hemorrhage without major complications and may be neuroprotective. Based on these results, planning of the ALISAH II, a Phase III, randomized, placebo-controlled trial to test the efficacy of albumin, is underway.URL: http://clinicaltrials.gov. Unique identifier: NCT00283400.

SUBMITTER: Suarez JI

PROVIDER: S-EPMC3288646 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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The Albumin in Subarachnoid Hemorrhage (ALISAH) multicenter pilot clinical trial: safety and neurologic outcomes.

Suarez Jose I JI Martin Renee H RH Calvillo Eusebia E Dillon Catherine C Bershad Eric M EM Macdonald R Loch RL Wong John J Harbaugh Robert R

Stroke 20120119 3

<h4>Background and purpose</h4>Human albumin has been shown to exert neuroprotective effects in animal models of cerebral ischemia and humans with various intracranial pathologies. We investigated the safety and tolerability of 25% human albumin in patients with subarachnoid hemorrhage.<h4>Methods</h4>The Albumin in Subarachnoid Hemorrhage (ALISAH) Pilot Clinical Trial was an open-label, dose-escalation study. We intended to study 4 different dosages of albumin of increasing magnitude (0.625 g/k ...[more]

PMID: 22267829

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Project description:Background/objectiveUncontrolled systemic inflammation after non-traumatic subarachnoid hemorrhage (SAH) is associated with worse outcomes. Changes in the peripheral eosinophil count have been linked to worse clinical outcomes after ischemic stroke, intracerebral hemorrhage, and traumatic brain injury. We aimed to investigate the association of eosinophil counts with clinical outcomes after SAH.MethodsThis retrospective observational study included patients with SAH admitted from January 2009 to July 2016. Variables included demographics, modified Fisher scale (mFS), Hunt-Hess Scale (HHS), global cerebral edema (GCE), and the presence of any infection. Peripheral eosinophil counts were examined as part of routine clinical care on admission and daily for 10 days after aneurysmal rupture. Outcome measures included dichotomized discharge mortality, modified Ranked Scale (mRS) score, delayed cerebral ischemia (DCI), vasospasm, and need for ventriculoperitoneal shunt (VPS). Statistical tests included the chi-square test, Student's t-test, and multivariable logistic regression (MLR) model.ResultsA total of 451 patients were included. The median age was 54 (IQR 45, 63) years, and 295 (65.4%) were female patients. On admission, 95 patients (21.1%) had a high HHS (>4), and 54 (12.0%) had GCE. A total of 110 (24.4%) patients had angiographic vasospasm, 88 (19.5%) developed DCI, 126 (27.9%) had an infection during hospitalization, and 56 (12.4%) required VPS. Eosinophil counts increased and peaked on days 8-10. Higher eosinophil counts on days 3-5 and day 8 were seen in patients with GCE (p < 0.05). Higher eosinophil counts on days 7-9 (p < 0.05) occurred in patients with poor discharge functional outcomes. In multivariable logistic regression models, higher day 8 eosinophil count was independently associated with worse discharge mRS (OR 6.72 [95% CI 1.27, 40.4], p = 0.03).ConclusionThis study demonstrated that a delayed increase in eosinophils after SAH occurs and may contribute to functional outcomes. The mechanism of this effect and the relationship with SAH pathophysiology merit further investigation.

Project description:Objective: Systemic inflammation after subarachnoid hemorrhage (SAH) is implicated in delayed cerebral ischemia (DCI) and adverse clinical outcomes. We hypothesize that early changes in peripheral leukocytes will be associated with outcomes after SAH. Methods: SAH patients admitted between January 2009 and December 2016 were enrolled into a prospective observational study and were assessed for Hunt Hess Scale (HHS) at admission, DCI, and modified Ranked Scale (mRS) at discharge. Total white blood cell (WBC) counts and each component of the differential cell count were determined on the day of admission (day 0) to 8 days after bleed (day 8). Global cerebral edema (GCE) was assessed on admission CT, and presence of any infection was determined. Statistical tests included student's t-test, Chi-square test, and multivariate logistic regression (MLR) models. Results: A total of 451 subjects were analyzed. Total WBCs and neutrophils decreased initially reaching a minimum at day 4-5 after SAH. Monocyte count increased gradually after SAH and peaked between day 6-8, while basophils and lymphocytes decreased initially from day 0 to 1 and steadily increased thereafter. Neutrophil to lymphocyte ratio (NLR) reached a peak on day 1 and decreased thereafter. WBCs, neutrophils, monocytes, and NLR were higher in patients with DCI and poor functional outcomes. WBCs, neutrophils, and NLR were higher in subjects who developed infections. In MLR models, neutrophils and monocytes were associated with DCI and worse functional outcomes, while NLR was only associated with worse functional outcomes. Occurrence of infection was associated with poor outcome. Neutrophils and NLR were associated with infection, while monocytes were not. Monocytes were higher in males, and ROC curve analysis revealed improved ability of monocytes to predict DCI and poor functional outcomes in male subjects. Conclusions: Monocytosis was associated with DCI and poor functional outcomes after SAH. The association between neutrophils and NLR and infection may impact outcomes. Early elevation in monocytes had an improved ability to predict DCI and poor functional outcomes in males, which was independent of the occurrence of infection.

Project description:Background Previous studies of patients with nontraumatic subarachnoid hemorrhage (SAH) suggest better outcomes at hospitals with higher case and procedural volumes, but the shape of the volume-outcome curve has not been defined. We sought to establish minimum volume criteria for SAH and aneurysm obliteration procedures that could be used for comprehensive stroke center certification. Methods and Results Data from 8512 discharges in the National Inpatient Sample (NIS) from 2010 to 2011 were analyzed using logistic regression models to evaluate the association between clinical outcomes (in-hospital mortality and the NIS-SAH Outcome Measure [NIS-SOM]) and measures of hospital annual case volume (nontraumatic SAH discharges, coiling, and clipping procedures). Sensitivity and specificity analyses for the association of desirable outcomes with different volume thresholds were performed. During 8512 SAH hospitalizations, 28.7% of cases underwent clipping and 20.1% underwent coiling with rates of 21.2% for in-hospital mortality and 38.6% for poor outcome on the NIS-SOM. The mean (range) of SAH, coiling, and clipping annual case volumes were 30.9 (1-195), 8.7 (0-94), and 6.1 (0-69), respectively. Logistic regression demonstrated improved outcomes with increasing annual case volumes of SAH discharges and procedures for aneurysm obliteration, with attenuation of the benefit beyond 35 SAH cases/year. Analysis of sensitivity and specificity using different volume thresholds confirmed these results. Analysis of previously proposed volume thresholds, including those utilized as minimum standards for comprehensive stroke center certification, showed that hospitals with more than 35 SAH cases annually had consistently superior outcomes compared with hospitals with fewer cases, although some hospitals below this threshold had similar outcomes. The adjusted odds ratio demonstrating lower risk of poor outcomes with SAH annual case volume ≥35 compared with 20 to 34 was 0.82 for the NIS-SOM (95% CI, 0.71-094; P=0.0054) and 0.80 (95% CI, 0.68-0.93; P=0.0055) for in-hospital mortality. Conclusions Outcomes for patients with SAH improve with increasing hospital case volumes and procedure volumes, with consistently better outcomes for hospitals with more than 35 SAH cases per year.

Project description:IntroductionAnaemia is common in aneurysmal subarachnoid haemorrhage (aSAH) and is a potential critical modifiable factor affecting secondary injury. Despite physiological evidence and management guidelines that support maintaining a higher haemoglobin level in patients with aSAH, current practice is one of a more restrictive approach to transfusion. The goal of this multicentre pilot trial is to determine the feasibility of successfully conducting a red blood cell (RBC) transfusion trial in adult patients with acute aSAH and anaemia (Hb ≤100 g/L), comparing a liberal transfusion strategy (Hb ≤100 g/L) with a restrictive strategy (Hb ≤80 g/L) on the combined rate of death and severe disability at 12 months.MethodsDesign This is a multicentre open-label randomised controlled pilot trial at 5 academic tertiary care centres. Population We are targeting adult aSAH patients within 14 days of their initial bleed and with anaemia (Hb ≤110 g/L). Randomisation Central computer-generated randomisation, stratified by centre, will be undertaken from the host centre. Randomisation into 1 of the 2 treatment arms will occur when the haemoglobin levels of eligible patients fall to ≤100 g/L. Intervention Patients will be randomly assigned to either a liberal (threshold: Hb ≤100 g/L) or a restrictive transfusion strategy (threshold: Hb ≤80 g/L). Outcome Primary: Centre randomisation rate over the study period. Secondary: (1) transfusion threshold adherence; (2) study RBC transfusion protocol adherence; and (3) outcome assessment including vital status at hospital discharge, modified Rankin Score at 6 and 12 months and Functional Independence Measure and EuroQOL Quality of Life Scale scores at 12 months. Outcome measures will be reported in aggregate.Ethics and disseminationThe study protocol has been approved by the host centre (OHSN-REB 20150433-01H). This study will determine the feasibility of conducting the large pragmatic RCT comparing 2 RBC transfusion strategies examining the effect of a liberal strategy on 12-month outcome following aSAH.Trial registration numberNCT02483351; Pre-results.

Project description:BackgroundNimodipine improves outcomes following aneurysmal subarachnoid hemorrhage (aSAH). Guidelines recommend that all patients should receive a fixed-dose nimodipine for 21 days. However, studies reported variability of nimodipine concentrations in aSAH. It is not clear if reduced systemic exposure contributes to worsening outcomes. The aim of this study was to compare nimodipine systemic exposure in those who experienced poor outcomes to those who experienced favorable outcomes.MethodsThis was a pilot prospective observational study in 30 adult patients admitted to the University of Alberta Hospital with aSAH. Data were collected from the electronic health records following enrollment. Blood samples were collected around one nimodipine 60 mg dose at a steady state, and nimodipine [total, (+)-R and (-)-S enantiomers] plasma concentrations were determined. The poor outcome was defined as a modified Rankin Scale (mRS) score at 90 days of 3-6, while the favorable outcome was an mRS score of 0-2. The correlation between nimodipine concentrations and percent changes in mean arterial pressure (MAP) before and after nimodipine administration was also determined. Furthermore, covariates potentially associated with nimodipine exposure were explored.ResultsIn total, 20 (69%) participants had favorable outcomes and 9 (31%) had poor outcomes. Following the exclusion of those with delayed presentation (>96 h from aSAH onset), among those presented with the World Federation of Neurological Surgeons (WFNS) grade 3-5, nimodipine median (interquartile range) area under the concentration time curve (AUC0-3h) in those with favorable outcomes were 4-fold higher than in those with poor outcomes [136 (52-192) vs. 33 (23-39) ng.h/mL, respectively, value of p = 0.2]. On the other hand, among those presented with WFNS grade 1-2, nimodipine AUC0-3h in those with favorable outcomes were significantly lower than in those with poor outcomes [30 (28-36) vs. 172 (117-308) ng.h/mL, respectively, value of p = 0.03)]. (+)-R-nimodipine AUC0-3h in those who did not develop vasospasm were 4-fold significantly higher than those who had vasospasm (value of p = 0.047). (-)-S-nimodipine was significantly correlated with percentage MAP reduction. Similar results were obtained when the whole cohort was analyzed.ConclusionThe study was the first to investigate the potential association between nimodipine exposure following oral dosing and outcomes. In addition, it suggests differential effects of nimodipine enantiomers, shedding light on the potential utility of nimodipine enantiomers. Larger studies are needed.

Dataset Information

The Albumin in Subarachnoid Hemorrhage (ALISAH) multicenter pilot clinical trial: safety and neurologic outcomes.

Publications

The Albumin in Subarachnoid Hemorrhage (ALISAH) multicenter pilot clinical trial: safety and neurologic outcomes.

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